The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling play important roles in a number of important biologic responses, including immune function, cellular growth, differentiation, and hematopoieses (Cooney, Shock 17:83-90, 2002).
It has been reported that abnormalities of the JAK/STAT pathway are associated with cancer (Garcia, et al., Cell Growth Differ. 8:1267-1276, 1997; Ihle Nature 377:591-594, 1995; Boudny & Kovarik Neoplasma 49:349-355, 2002; Li & Shaw J. Biol. Chem. 277:17397-17405, 2002; Kaur, et al., Cell Signal 14:419-429, 2002). For example, constitutive activation of the MK was found in T-cell childhood acute lymphoblastic leukemia (Lacronique, et al., Science 278:1309-1312, 1997). Transfection of a constitutively activated STAT3 results in tumorigenicity in nude mice (Bromberg, et al., Cell 98:295-303, 1999). Constitutive activation of STAT3 correlates with cell proliferation in breast carcinoma (Zhang, et al., Oncogene 22:894-905, 2003) and non-small-cell lung cancer (NSCLC) (He, et al., Biochem. Biophys. Res. Commun. 301:386-391, 2003). On the other hand, inhibition of JAK/STAT signaling results in suppression of cancer cell growth and induces apoptosis in various cancer types (Zhang, et al., Oncogene 22:894-905, 2003; Blaskovich, et al., Cancer Res. 63:1270-1279, 2003; Yamashita, et al., Oncogene 22:1638-1652, 2003; Kanai, et al., Oncogene 22:548-554, 2003; Mora, et al., Cancer Res. 62:6659-6666, 2002; Buettner, et al., Clin Cancer Res. 8:945-954, 2002).
SOCS gene family proteins function as negative regulators of the JAK/STAT signaling pathway (O'Shea, et al., Cell 109 Suppl:S121-S131, 2002, Aaronson & Horvath Science 296:1653-1655, 2002). Eight proteins, CIS and SOCS1-SOCS7, have been identified in the suppressors of cytokine signaling (SOCS) family. They contain a central SH2 domain, a conserved C-terminus (the SOCS box), and a unique N-terminus (Masuhara, et al., Biochem. Biophys. Res. Commun. 239:439-446, 1997; Hilton, et al., Proc. Natl. Acad. Sci. USA 95:114-119, 1998; O'Shea, et al., Cell 109 Suppl:S121-S131, 2002). Expression of SOCS-1 to −3 and CIS is induced by cytokine or growth factor stimulation, which directly antagonizes STAT activation as part of a classic feedback loop (O'Shea, et al., Cell 109 Suppl:S121-S131, 2002, Aaronson & Horvath Science 296:1653-1655, 2002). Ectopic expression of SOCS-1 gene has been shown to be able to block the transforming activity of oncogenic forms of JAK, in addition to its physiology role in inhibiting cytokine signaling (Frantsve, et al., Mol. Cell. Biol. 21:3547-3557, 2001).
Aberrant hypermethylation of promoter regions in CpG islands has been shown to be associated with transcriptional silencing of the genes in various cancers (Laird, Nat. Rev. Cancer 3:253-266, 2003). For example, such hypermethylation has been recognized as a mechanism for inactivating various tumor suppressor genes in cancer (Jaenisch & Bird, Nat. Genet. 33 Suppl:245-254, 2003; Esteller, et al., Science 297:1807-1808, 2002). These gene include VHL (Herman, et al., Proc. Natl. Acad. Sci. USA 91:9700-9704; 1994), MGMT (Esteller, et al, Cancer Res. 59:793-797, 1999), MLH1 (Herman, et al., Proc. Natl. Acad. Sci. USA 95:6870-6875, 1998), DAPK1 (Katzenellenbogen, et al, Blood 93:4347-4353, 1999) and SFRPs (Suzuki, et al., Nat. Genet. 31:141-149, 2002). Recently, involvement of SOCS-1 in carcinogenesis has also been reported. SOCS-1 was found frequently silenced by hypermethylation in hapatocellular carcinoma (HCC) (Yoshikawa, et al., Nat. Genet. 28:29-35, 2001), multiple myeloma (Galm, et al., Blood 101:2784-2788, 2003) and hepatoblastomas (Nagai, et al., J. Hum. Genet. 48:65-69, 2003). SOCS-1 appears to have tumor suppressor activity (Rottapel, et al., Oncogene 21:4351-4362, 2002) and restoration of the SOCS-1 gene in HCC cells causes growth suppression and induction of apoptosis (Yoshikawa, et al., Nat. Genet. 28:29-35, 2001). However, the prior art has not shown that SOCS-3 play a role in cancers such as lung cancer or breast and cancer and moreover, has not shown a role of methylation of SOCS3 in cancer.